SummaryIn contrast to mammals, newts possess exceptional capacities among vertebrates to rebuild complex structures, such as the brain. Our goal is to bridge the gap in the regenerative outcomes between newts and mammals. My group has made significant contributions towards this goal. We created a novel experimental system, which recapitulates central features of Parkinson’s disease in newts, and provides a unique model for understanding regeneration in the adult midbrain. We showed an unexpected but key feature of the newt brain that it is akin to the mammalian brain in terms of the extent of homeostatic cell turn over, but distinct in terms of its injury response, showing the regenerative capacity of the adult vertebrate brain by activating neurogenesis in normally quiescent regions. Further we established a critical role for the neurotransmitter dopamine in controlling quiescence in the midbrain, thereby preventing neurogenesis during homeostasis and terminating neurogenesis once the correct number of neurons has been produced during regeneration. Here we aim to identify key molecular pathways that regulate adult neurogenesis, to define lineage relationships between neuronal stem and progenitor cells, and to identify essential differences between newts and mammals. We will combine pharmacological modulation of neurotransmitter signaling with extensive cellular fate mapping approaches, and molecular manipulations. Ultimately we will test hypotheses derived from newt studies with mammalian systems including newt/mouse cross species complementation approaches. We expect that our findings will provide new regenerative strategies, and reveal fundamental aspects of cell fate determination, tissue growth, and tissue maintenance in normal and pathological conditions.

In contrast to mammals, newts possess exceptional capacities among vertebrates to rebuild complex structures, such as the brain. Our goal is to bridge the gap in the regenerative outcomes between newts and mammals. My group has made significant contributions towards this goal. We created a novel experimental system, which recapitulates central features of Parkinson’s disease in newts, and provides a unique model for understanding regeneration in the adult midbrain. We showed an unexpected but key feature of the newt brain that it is akin to the mammalian brain in terms of the extent of homeostatic cell turn over, but distinct in terms of its injury response, showing the regenerative capacity of the adult vertebrate brain by activating neurogenesis in normally quiescent regions. Further we established a critical role for the neurotransmitter dopamine in controlling quiescence in the midbrain, thereby preventing neurogenesis during homeostasis and terminating neurogenesis once the correct number of neurons has been produced during regeneration. Here we aim to identify key molecular pathways that regulate adult neurogenesis, to define lineage relationships between neuronal stem and progenitor cells, and to identify essential differences between newts and mammals. We will combine pharmacological modulation of neurotransmitter signaling with extensive cellular fate mapping approaches, and molecular manipulations. Ultimately we will test hypotheses derived from newt studies with mammalian systems including newt/mouse cross species complementation approaches. We expect that our findings will provide new regenerative strategies, and reveal fundamental aspects of cell fate determination, tissue growth, and tissue maintenance in normal and pathological conditions.

Max ERC Funding

1 500 000 €

Duration

Start date: 2012-02-01, End date: 2017-01-31

Project acronymCACTUS

Projectdevelopmental social Cognition and ACTion UnderStanding

Researcher (PI)Kjell Gustaf Gredebäck

Host Institution (HI)UPPSALA UNIVERSITET

Call DetailsStarting Grant (StG), SH4, ERC-2012-StG_20111124

SummaryHumans are social creatures throughout life. This proposal aims to advance our knowledge of the mechanisms that mediate understanding of others’ actions from a developmental perspective. A special emphasis will be devoted to mirror neuron and teleological frameworks. The former framework focuses on reciprocal motor activation during action execution and observation whereas the later framework emphasizes the application of abstract principles to observed events. The mechanisms that guide both processes will be investigated in isolation, but special attention will also be devoted to understanding how these diverse forms of action understanding jointly contribute to action understanding. The project encompasses three essential research objectives, illustrated by three research questions. How do mirror neuron and teleological processes influence action understanding? How does action understanding enable social action evaluation (empathy and pro-social preferences)? How is action understanding expressed during real-life social interactions? These questions will be addressed by presenting infants and toddlers with social events of varying complexity (from simple actions and animated sequences to complex everyday social events), relating empirical findings to predictions derived from the teleological and motor cognitive frameworks. The overarching aim is to provide a computational model of early emerging social cognitive capabilities, with a focus on action understanding and action evaluation, while passively observing others and while partaking in social interactions with others.

Humans are social creatures throughout life. This proposal aims to advance our knowledge of the mechanisms that mediate understanding of others’ actions from a developmental perspective. A special emphasis will be devoted to mirror neuron and teleological frameworks. The former framework focuses on reciprocal motor activation during action execution and observation whereas the later framework emphasizes the application of abstract principles to observed events. The mechanisms that guide both processes will be investigated in isolation, but special attention will also be devoted to understanding how these diverse forms of action understanding jointly contribute to action understanding. The project encompasses three essential research objectives, illustrated by three research questions. How do mirror neuron and teleological processes influence action understanding? How does action understanding enable social action evaluation (empathy and pro-social preferences)? How is action understanding expressed during real-life social interactions? These questions will be addressed by presenting infants and toddlers with social events of varying complexity (from simple actions and animated sequences to complex everyday social events), relating empirical findings to predictions derived from the teleological and motor cognitive frameworks. The overarching aim is to provide a computational model of early emerging social cognitive capabilities, with a focus on action understanding and action evaluation, while passively observing others and while partaking in social interactions with others.

SummaryAccurate genome duplication is controlled by multi-subunit protein complexes which associate with chromatin and dictate when and where replication should take place. Dynamic changes in these complexes lie at the heart of their ability to ensure the maintenance of genomic integrity. Defects in origin bound complexes lead to re-replication of the genome across evolution, have been linked to DNA-replication stress and may predispose for gene amplification events. Such genomic aberrations are central to malignant transformation.
We wish to understand how once per cell cycle replication is normally controlled within the context of the living cell and how defects in this control may result in loss of genome integrity and provide genome plasticity. To this end, live cell imaging in human cells in culture will be combined with genetic studies in fission yeast and modelling and in silico analysis.
The proposed research aims to:
1. Decipher the regulatory mechanisms which act in time and space to ensure once per cell cycle replication within living cells and how they may be affected by system aberrations, using functional live cell imaging.
2. Test whether aberrations in the licensing system may provide a selective advantage, through amplification of multiple genomic loci. To this end, a natural selection experiment will be set up in fission yeast .
3. Investigate how rereplication takes place along the genome in single cells. Is there heterogeneity amongst a population, leading to a plethora of different genotypes? In silico analysis of full genome DNA rereplication will be combined to single cell analysis in fission yeast.
4. Assess the relevance of our findings for gene amplification events in cancer. Does ectopic expression of human Cdt1/Cdc6 in cancer cells enhance drug resistance through gene amplification?
Our findings are expected to offer novel insight into mechanisms underlying cancer development and progression.

Accurate genome duplication is controlled by multi-subunit protein complexes which associate with chromatin and dictate when and where replication should take place. Dynamic changes in these complexes lie at the heart of their ability to ensure the maintenance of genomic integrity. Defects in origin bound complexes lead to re-replication of the genome across evolution, have been linked to DNA-replication stress and may predispose for gene amplification events. Such genomic aberrations are central to malignant transformation.
We wish to understand how once per cell cycle replication is normally controlled within the context of the living cell and how defects in this control may result in loss of genome integrity and provide genome plasticity. To this end, live cell imaging in human cells in culture will be combined with genetic studies in fission yeast and modelling and in silico analysis.
The proposed research aims to:
1. Decipher the regulatory mechanisms which act in time and space to ensure once per cell cycle replication within living cells and how they may be affected by system aberrations, using functional live cell imaging.
2. Test whether aberrations in the licensing system may provide a selective advantage, through amplification of multiple genomic loci. To this end, a natural selection experiment will be set up in fission yeast .
3. Investigate how rereplication takes place along the genome in single cells. Is there heterogeneity amongst a population, leading to a plethora of different genotypes? In silico analysis of full genome DNA rereplication will be combined to single cell analysis in fission yeast.
4. Assess the relevance of our findings for gene amplification events in cancer. Does ectopic expression of human Cdt1/Cdc6 in cancer cells enhance drug resistance through gene amplification?
Our findings are expected to offer novel insight into mechanisms underlying cancer development and progression.

Max ERC Funding

1 531 000 €

Duration

Start date: 2012-02-01, End date: 2017-01-31

Project acronymELSI

ProjectEmotional Learning in Social Interaction

Researcher (PI)Andreas Olsson

Host Institution (HI)KAROLINSKA INSTITUTET

Call DetailsStarting Grant (StG), SH4, ERC-2011-StG_20101124

SummaryThis project will open up new horizons in the study of emotional learning by describing and modeling its role in social interaction. It brings together a novel set of experimental manipulations with two hitherto unconnected lines of research; biology of aversive learning and social cognition, with the aim to answer four specific objectives, namely to identify the mechanisms of aversive learning (1) about others and its dependence on stimulus bound (e.g. ethnic group belonging) and conceptual (e.g. moral and social status) features; (2) from others through observation, and its dependence on processing of stimulus bound (e.g. emotional expressiveness) and conceptual (e.g. empathy and mental state attributions) features; (3) during interaction and its dependence social characteristics as described in 1 and 2; and (4) build and test a neural model of social-emotional learning. To achieve these objectives, this project proposes a multi-method research program using novel behavioral experimental paradigms and manipulated virtual environments, drawing on cognitive neuroscience, psychophysiology, and behavioral genetics. It is predicted that social emotional learning will be accomplished through the interaction of four, partially overlapping, neural networks coding for affective, associative, social cognitive and instrumental/goal directed aspects, respectively. Whereas it is expected that the two first networks will be common to classical conditioning and social learning, the latter is hypothesized to be distinguished by its reliance on the social-cognitive network. The fourth network is predicted to be integral to the social learning through interactions and the shaping of behavioral norms. The proposed research will enhance our understanding of important social phenomena, such as the emergence and maintanance of group conflicts and norm compliance. It will also shed light on common psychological disorders, such as social anxiety, autism and psychopathy that are characterized by dysfunctions of the social emotional learning system.

This project will open up new horizons in the study of emotional learning by describing and modeling its role in social interaction. It brings together a novel set of experimental manipulations with two hitherto unconnected lines of research; biology of aversive learning and social cognition, with the aim to answer four specific objectives, namely to identify the mechanisms of aversive learning (1) about others and its dependence on stimulus bound (e.g. ethnic group belonging) and conceptual (e.g. moral and social status) features; (2) from others through observation, and its dependence on processing of stimulus bound (e.g. emotional expressiveness) and conceptual (e.g. empathy and mental state attributions) features; (3) during interaction and its dependence social characteristics as described in 1 and 2; and (4) build and test a neural model of social-emotional learning. To achieve these objectives, this project proposes a multi-method research program using novel behavioral experimental paradigms and manipulated virtual environments, drawing on cognitive neuroscience, psychophysiology, and behavioral genetics. It is predicted that social emotional learning will be accomplished through the interaction of four, partially overlapping, neural networks coding for affective, associative, social cognitive and instrumental/goal directed aspects, respectively. Whereas it is expected that the two first networks will be common to classical conditioning and social learning, the latter is hypothesized to be distinguished by its reliance on the social-cognitive network. The fourth network is predicted to be integral to the social learning through interactions and the shaping of behavioral norms. The proposed research will enhance our understanding of important social phenomena, such as the emergence and maintanance of group conflicts and norm compliance. It will also shed light on common psychological disorders, such as social anxiety, autism and psychopathy that are characterized by dysfunctions of the social emotional learning system.

SummaryThis project will break new ground in the language sciences by pursuing a linguistic inquiry into landscape. From the linguist s point of view, the geophysical environment is virtually unexplored. Yet it has vast potential for influence on the discipline. The project will play a pioneering role in situating landscape within linguistics as a fundamental domain of representational systems, opening up important links to other disciplines concerned with landscape that usually have little to do with language. It will achieve this by (1) exploring landscape categorization in a number of languages, (2) comparing such categorization, (3) developing a model for understanding categorization across languages and speakers, and (4) documenting vanishing landscape systems. The research team will study landscape categorization in six diverse language settings. Each setting is a case study carried out by a team member with expert knowledge and prior field experience of the setting. Each setting offers opportunities of studying closely related languages as well as individuals speaking the same language, making comparison possible not only among maximally diverse languages but also at finer levels of linguistic granularity. An exploratory psycholinguistic subproject will probe the relationship between language and cognition in the landscape domain. The project will blaze a trail in applying GIS to linguistic data, in testing advanced experimental techniques in the field, and in documenting domain-specific data from a global language sample. Cross-cultural variation in landscape ontology is a matter of great practical importance understanding the meaning and reference of landscape terms and place names is crucial to major fields of human cooperation, from navigation to international law.

This project will break new ground in the language sciences by pursuing a linguistic inquiry into landscape. From the linguist s point of view, the geophysical environment is virtually unexplored. Yet it has vast potential for influence on the discipline. The project will play a pioneering role in situating landscape within linguistics as a fundamental domain of representational systems, opening up important links to other disciplines concerned with landscape that usually have little to do with language. It will achieve this by (1) exploring landscape categorization in a number of languages, (2) comparing such categorization, (3) developing a model for understanding categorization across languages and speakers, and (4) documenting vanishing landscape systems. The research team will study landscape categorization in six diverse language settings. Each setting is a case study carried out by a team member with expert knowledge and prior field experience of the setting. Each setting offers opportunities of studying closely related languages as well as individuals speaking the same language, making comparison possible not only among maximally diverse languages but also at finer levels of linguistic granularity. An exploratory psycholinguistic subproject will probe the relationship between language and cognition in the landscape domain. The project will blaze a trail in applying GIS to linguistic data, in testing advanced experimental techniques in the field, and in documenting domain-specific data from a global language sample. Cross-cultural variation in landscape ontology is a matter of great practical importance understanding the meaning and reference of landscape terms and place names is crucial to major fields of human cooperation, from navigation to international law.

Max ERC Funding

1 499 931 €

Duration

Start date: 2011-03-01, End date: 2016-02-29

Project acronymNeurogenesis

ProjectExploration and promotion of neurogenesis in the adult brain

Researcher (PI)Jonas FRISÉN

Host Institution (HI)KAROLINSKA INSTITUTET

Call DetailsAdvanced Grant (AdG), LS3, ERC-2015-AdG

SummaryIt is now well established that new neurons are added to certain regions of the adult brain. There is today considerable interest in the development of regenerative therapies based on modulating endogenous neurogenesis, but it is necessary to better understand these events to assess whether this is rational and realistic.
This application takes its initiation in two recent discoveries that we have made: that astrocytes in the mouse striatum give rise to new neurons after stroke or inhibition of Notch signaling (Magnusson et al., Science, 2014) and that neurogenesis is a continuous process in the human striatum throughout adulthood (Ernst et al., Cell, 2014). We propose to characterize the molecular regulation of neurogenesis from striatal astrocytes in detail, and compare these astrocytes with those in other regions to understand why striatal astrocytes are uniquely neurogenic and whether astrocytes in other parts of the brain can be induced to give rise to new neurons. We will, moreover, assess the role of integration of new neurons in the striatal circuitry by inducing neurogenesis in the striatum in adult mice by blocking Notch signaling or by inducing stroke and modulate the activity of the new neurons by optogenetics and chemogenetics. We will, furthermore, study whether striatal neurogenesis is altered in human neurological diseases by retrospective birth dating by measuring the integration of 14C from nuclear bomb tests. We will assess whether inducing striatal neurogenesis in corresponding mouse models of neurological diseases has therapeutic potential.
This project will elucidate the molecular regulation of neurogenesis from astrocytes and the neurogenic potential of astrocytes in different parts of the brain, reveal the role of new neurons in the striatum, answer whether striatal neurogenesis is altered in common neurological conditions in humans and reveal whether inducing striatal neurogenesis may have therapeutic potential.

It is now well established that new neurons are added to certain regions of the adult brain. There is today considerable interest in the development of regenerative therapies based on modulating endogenous neurogenesis, but it is necessary to better understand these events to assess whether this is rational and realistic.
This application takes its initiation in two recent discoveries that we have made: that astrocytes in the mouse striatum give rise to new neurons after stroke or inhibition of Notch signaling (Magnusson et al., Science, 2014) and that neurogenesis is a continuous process in the human striatum throughout adulthood (Ernst et al., Cell, 2014). We propose to characterize the molecular regulation of neurogenesis from striatal astrocytes in detail, and compare these astrocytes with those in other regions to understand why striatal astrocytes are uniquely neurogenic and whether astrocytes in other parts of the brain can be induced to give rise to new neurons. We will, moreover, assess the role of integration of new neurons in the striatal circuitry by inducing neurogenesis in the striatum in adult mice by blocking Notch signaling or by inducing stroke and modulate the activity of the new neurons by optogenetics and chemogenetics. We will, furthermore, study whether striatal neurogenesis is altered in human neurological diseases by retrospective birth dating by measuring the integration of 14C from nuclear bomb tests. We will assess whether inducing striatal neurogenesis in corresponding mouse models of neurological diseases has therapeutic potential.
This project will elucidate the molecular regulation of neurogenesis from astrocytes and the neurogenic potential of astrocytes in different parts of the brain, reveal the role of new neurons in the striatum, answer whether striatal neurogenesis is altered in common neurological conditions in humans and reveal whether inducing striatal neurogenesis may have therapeutic potential.

Max ERC Funding

2 500 000 €

Duration

Start date: 2016-10-01, End date: 2021-09-30

Project acronymPAGE

ProjectThe role of mRNA-processing bodies in ageing

Researcher (PI)Popi Syntichaki

Host Institution (HI)IDRYMA IATROVIOLOGIKON EREUNON AKADEMIAS ATHINON

Call DetailsStarting Grant (StG), LS3, ERC-2007-StG

SummaryRecently, we and others have revealed that, in the nematode Caenorhabditis elegans, reduction of protein synthesis rates in somatic cells extends lifespan. Based on this, we postulate that the molecular factors and mechanisms that control the mRNA metabolism in post-mitotic cells are critical determinants of ageing. This project will validate this hypothesis using C. elegans as main model system, but parallel studies in Saccharomyces cerevisiae and Drosophila melanogaster will prove the conservation of our observations. The cellular factors involved in mRNA metabolism (degradation/storage) are localized at specific particles in the cytoplasm of all eukaryotic cells, termed mRNA processing (P) bodies. Additionally, stress granules are cytoplasmic sites of mRNA-metabolism that are formed under stress conditions in mammalian cells. The objectives of this project include: -Monitoring of both P bodies and stress granules in adult worms and characterization of the age-related alterations in their profile, by immunostaining and real-time fluorescence imaging -Direct alterations in the expression of genes encoding factors of each particle in wild-type worms and analysis of the effects on lifespan and stress resistance -Comparison of the age-related changes in the profile of P bodies and stress granules between wild-type and long- or short-lived mutant worms -Direct alterations in the expression of genes encoding factors of each particle in worms with altered lifespan and investigation of the effects on lifespan and stress resistance -Observation of the age-related alterations in the profile of P bodies in yeast and flies, both in wild-type and long-lived strains. The rationale for this project is to provide insight into the modulation of ageing and stress resistance at the level of mRNA metabolism, which is a yet unexplored field of the biology of ageing and global stress response.

Recently, we and others have revealed that, in the nematode Caenorhabditis elegans, reduction of protein synthesis rates in somatic cells extends lifespan. Based on this, we postulate that the molecular factors and mechanisms that control the mRNA metabolism in post-mitotic cells are critical determinants of ageing. This project will validate this hypothesis using C. elegans as main model system, but parallel studies in Saccharomyces cerevisiae and Drosophila melanogaster will prove the conservation of our observations. The cellular factors involved in mRNA metabolism (degradation/storage) are localized at specific particles in the cytoplasm of all eukaryotic cells, termed mRNA processing (P) bodies. Additionally, stress granules are cytoplasmic sites of mRNA-metabolism that are formed under stress conditions in mammalian cells. The objectives of this project include: -Monitoring of both P bodies and stress granules in adult worms and characterization of the age-related alterations in their profile, by immunostaining and real-time fluorescence imaging -Direct alterations in the expression of genes encoding factors of each particle in wild-type worms and analysis of the effects on lifespan and stress resistance -Comparison of the age-related changes in the profile of P bodies and stress granules between wild-type and long- or short-lived mutant worms -Direct alterations in the expression of genes encoding factors of each particle in worms with altered lifespan and investigation of the effects on lifespan and stress resistance -Observation of the age-related alterations in the profile of P bodies in yeast and flies, both in wild-type and long-lived strains. The rationale for this project is to provide insight into the modulation of ageing and stress resistance at the level of mRNA metabolism, which is a yet unexplored field of the biology of ageing and global stress response.

Max ERC Funding

1 080 000 €

Duration

Start date: 2008-09-01, End date: 2014-08-31

Project acronymQUALIAGE

ProjectSpatial protein quality control and its links to aging, proteotoxicity, and polarity

Researcher (PI)Lars Bertil Thomas Nyström

Host Institution (HI)GOETEBORGS UNIVERSITET

Call DetailsAdvanced Grant (AdG), LS3, ERC-2010-AdG_20100317

SummaryPropagation of a species requires periodic cell renewal to avoid clonal senescence. My
laboratory has described a new mechanism for such cell renewal in yeast, in which damaged
protein aggregates are transported out of the daughter buds along actin cables to preserve
youthfulness. Such spatial protein quality control (SQC) is a Sir2p-dependent process and by establishing the global genetic interaction network of SIR2, we identified the
polarisome as the machinery required for mitotic segregation and translocation of protein
aggregates. In addition, we found that the fusion of smaller aggregates into large inclusion
bodies, a process that has been suggested to reduce the toxicity of such aggregates, requires
actin cables and their nucleation at the septin ring. Sir2p controls damage segregation by
affecting deacetylation and the activity of the chaperonin CCT, enhancing actin folding and
polymerization. Considering that CCT has been implicated in mitigating
aggregation/toxicity of polyglutamine proteins, e.g. huntingtin, and that actin cables is
affecting formation, fusion, and resolution of aggregates, we hypothesize that CCT
deacetylation may underlie Sirt1¿s (mammalian orthologues of Sir2p) documented beneficial
effects in several neurodegenerative disorders caused by proteotoxic aggregates. This project
is aimed at approaching this hypothesis and to elucidate, on a genome-wide scale, how the
cell tether, sort, fuse, and detoxify aggregates with the help of CCT, actin cables, and the
polarity machinery. This will be accomplished by combining the power of synthetic genetic
array analysis, high-content imaging, genome wide proximity ligand assays, and microfluidics.
Using such approaches, the project seeks to decipher the machineries of the spatial quality
control network as a means to identify new therapeutic targets that may retard or postpone
the development of age-related maladies, including neurodegenerative disorders.

Propagation of a species requires periodic cell renewal to avoid clonal senescence. My
laboratory has described a new mechanism for such cell renewal in yeast, in which damaged
protein aggregates are transported out of the daughter buds along actin cables to preserve
youthfulness. Such spatial protein quality control (SQC) is a Sir2p-dependent process and by establishing the global genetic interaction network of SIR2, we identified the
polarisome as the machinery required for mitotic segregation and translocation of protein
aggregates. In addition, we found that the fusion of smaller aggregates into large inclusion
bodies, a process that has been suggested to reduce the toxicity of such aggregates, requires
actin cables and their nucleation at the septin ring. Sir2p controls damage segregation by
affecting deacetylation and the activity of the chaperonin CCT, enhancing actin folding and
polymerization. Considering that CCT has been implicated in mitigating
aggregation/toxicity of polyglutamine proteins, e.g. huntingtin, and that actin cables is
affecting formation, fusion, and resolution of aggregates, we hypothesize that CCT
deacetylation may underlie Sirt1¿s (mammalian orthologues of Sir2p) documented beneficial
effects in several neurodegenerative disorders caused by proteotoxic aggregates. This project
is aimed at approaching this hypothesis and to elucidate, on a genome-wide scale, how the
cell tether, sort, fuse, and detoxify aggregates with the help of CCT, actin cables, and the
polarity machinery. This will be accomplished by combining the power of synthetic genetic
array analysis, high-content imaging, genome wide proximity ligand assays, and microfluidics.
Using such approaches, the project seeks to decipher the machineries of the spatial quality
control network as a means to identify new therapeutic targets that may retard or postpone
the development of age-related maladies, including neurodegenerative disorders.

Max ERC Funding

2 371 262 €

Duration

Start date: 2011-06-01, End date: 2016-05-31

Project acronymREBOOT

ProjectReleasing the brakes on adult plasticity

Researcher (PI)Martin Lövdén

Host Institution (HI)KAROLINSKA INSTITUTET

Call DetailsConsolidator Grant (CoG), SH4, ERC-2013-CoG

SummaryAge-related cognitive impairments compromise the functional capacity of aging individuals, and create major individual and societal costs. Developing means for preserving and restoring cognitive functioning in old age is therefore of great importance. Age-related cognitive impairments have a complex and multifactorial etiology. Pharmaceutical approaches to prevention and treatment have therefore been unsuccessful, and searching for non-pharmaceutical approaches is important. Results of cognitive training studies have so far been disappointing. I hypothesize that the reason for this is that plasticity is functionally inhibited after normal childhood development. Plasticity is then further reduced in aging due to negative brain changes. In this sense, past studies on the effects of cognitive training in adulthood and old age have, so to speak, attempted to push a car that has the brakes on. In a series of experimental studies on humans, my research team will discover feasible ways to release inhibitory brakes on adult plasticity, develop routes to attenuate age-related negative effects on plasticity, and uncover the neural mediators of training-related change in performance, so that the effects of cognitive training can be increased and better understood. Outcome variables include measures of brain function, volume, and integrity acquired using high-resolution magnetic resonance imaging, and up-to-date measures of cognitive performance. Experimental effects on these measures will be evaluated using structural equation models suitable for analyzing repeated measures. This amalgamation of state-of-the-art methodology in the neurosciences and the behavioral sciences bolsters the uniqueness of this research program, which will enlighten the mechanisms of plasticity at neuronal and behavioral levels of analysis. The resulting insights will pave the way for effective rehabilitation of several neurological conditions and for reducing age-associated cognitive impairments.

Age-related cognitive impairments compromise the functional capacity of aging individuals, and create major individual and societal costs. Developing means for preserving and restoring cognitive functioning in old age is therefore of great importance. Age-related cognitive impairments have a complex and multifactorial etiology. Pharmaceutical approaches to prevention and treatment have therefore been unsuccessful, and searching for non-pharmaceutical approaches is important. Results of cognitive training studies have so far been disappointing. I hypothesize that the reason for this is that plasticity is functionally inhibited after normal childhood development. Plasticity is then further reduced in aging due to negative brain changes. In this sense, past studies on the effects of cognitive training in adulthood and old age have, so to speak, attempted to push a car that has the brakes on. In a series of experimental studies on humans, my research team will discover feasible ways to release inhibitory brakes on adult plasticity, develop routes to attenuate age-related negative effects on plasticity, and uncover the neural mediators of training-related change in performance, so that the effects of cognitive training can be increased and better understood. Outcome variables include measures of brain function, volume, and integrity acquired using high-resolution magnetic resonance imaging, and up-to-date measures of cognitive performance. Experimental effects on these measures will be evaluated using structural equation models suitable for analyzing repeated measures. This amalgamation of state-of-the-art methodology in the neurosciences and the behavioral sciences bolsters the uniqueness of this research program, which will enlighten the mechanisms of plasticity at neuronal and behavioral levels of analysis. The resulting insights will pave the way for effective rehabilitation of several neurological conditions and for reducing age-associated cognitive impairments.

Max ERC Funding

1 918 070 €

Duration

Start date: 2014-07-01, End date: 2019-06-30

Project acronymSELF-UNITY

ProjectThe Unity of the Bodily Self

Researcher (PI)Hans Henrik EHRSSON

Host Institution (HI)KAROLINSKA INSTITUTET

Call DetailsAdvanced Grant (AdG), SH4, ERC-2017-ADG

SummaryHow do we come to experience ourselves as single physical entities? Under normal healthy conditions, we humans always experience a single body as our own physical self, and this bodily self is undivided and perceived as a single whole. But what cognitive processes and brain mechanisms mediate this unity of the bodily self? This fundamental question has long been beyond the reach of experimental studies because of the lack of behavioral paradigms that allow controlled manipulation of basic components of the self-unity. To address this issue, we here propose the use of novel full-body illusion paradigms to “fragment”, “duplicate” or “split” the sense of bodily self during well-controlled behavioral and neuroimaging experiments. By studying the behavioral and neural principles that determine specific illusory changes in perceived self-unity, we can elucidate much about the neurocognitive mechanisms that support the sense of having a single unitary bodily self under normal conditions. Our pioneering behavioral paradigms utilize the newest virtual reality technologies, and these are combined with multimodal neuroimaging using the most advanced analysis methods, such as multivariate pattern recognition. The aims of the project are to unravel (i) how we come to experience a single bodily self as opposed to multiple ones; (ii) how we perceive a coherent bodily self instead of fragmented parts; and (iii) how information from different sensory modalities – including vestibular and interoceptive signals – are integrated to achieve this coherent sense of a singular bodily self. The new basic knowledge generated by this project will be important for future clinical neuroscience research into major psychiatric and neurological disorders with disturbances in self-unity, such as schizophrenia, dissociative disorders and stroke with body neglect, by providing novel ideas for hypotheses about the involved neurocognitive pathophysiology.

How do we come to experience ourselves as single physical entities? Under normal healthy conditions, we humans always experience a single body as our own physical self, and this bodily self is undivided and perceived as a single whole. But what cognitive processes and brain mechanisms mediate this unity of the bodily self? This fundamental question has long been beyond the reach of experimental studies because of the lack of behavioral paradigms that allow controlled manipulation of basic components of the self-unity. To address this issue, we here propose the use of novel full-body illusion paradigms to “fragment”, “duplicate” or “split” the sense of bodily self during well-controlled behavioral and neuroimaging experiments. By studying the behavioral and neural principles that determine specific illusory changes in perceived self-unity, we can elucidate much about the neurocognitive mechanisms that support the sense of having a single unitary bodily self under normal conditions. Our pioneering behavioral paradigms utilize the newest virtual reality technologies, and these are combined with multimodal neuroimaging using the most advanced analysis methods, such as multivariate pattern recognition. The aims of the project are to unravel (i) how we come to experience a single bodily self as opposed to multiple ones; (ii) how we perceive a coherent bodily self instead of fragmented parts; and (iii) how information from different sensory modalities – including vestibular and interoceptive signals – are integrated to achieve this coherent sense of a singular bodily self. The new basic knowledge generated by this project will be important for future clinical neuroscience research into major psychiatric and neurological disorders with disturbances in self-unity, such as schizophrenia, dissociative disorders and stroke with body neglect, by providing novel ideas for hypotheses about the involved neurocognitive pathophysiology.